Thiophanate-methyl

Endpoint summary

Description of key information

In the acute oral toxicity study no adverse effects have been observed and a discriminating dose > 5000 mg/kg bw was determined for rats. The substance was tested for inhalation toxicity in rats in a 4 h whole-body inhalation study similar to OECD TG 403. The acute inhalation median lethal concentration (4hr LC50) was determined to be 1700 mg/m3 for males and 1900 mg/m3 for females.

The acute dermal LD50 was determined to be > 2000 mg/kg bw.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

21 May 1990 - 23 August 1990

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Crj: CD(SD)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Japan, Inc. (Atsugi, Kanagawa, Japan)
- Age at study initiation: 7 weeks old
- Weight at study initiation: 221.4 ± 2.2 g in males and 161.0 ± 10.2 g in females at administration
- Housing: Group-housed (5 animals per cage) in stainless steel mesh cage (W 21 xD 40 xH 19cm)
- Diet: Pelleted diet, MF(Oriental Yeast Co., Ltd., Tokyo), access to the food was prevented overnight before and 3 hours after the administration
- Water: tap water, ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.4 ± 0.2
- Humidity (%): 62.6 ± 2.4
- Air changes (per hr): 12
- Photoperiod (hrs dark / hrs light): 12 / 12

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

VEHICLE
- Amount of vehicle : 10 mL/kg bw

Doses:

5000 mg/kg bw

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Animals were observed for 1 hour and at 3 hours after the administration and thereafter at least once a day (except holidays). The animals were weighed prior to the administration and after 1, 2, 3, 7 and 14 days.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 5 000 mg/kg bw

Based on:

test mat.

Mortality:

No death was found in any rats. The oral LD50 values were determined as more than 5000 mg/kg in both sexes.

Clinical signs:

other: No clinical signs were observed in any rats of either sex.

Gross pathology:

No abnormality was observed in any rats of either sex.

Interpretation of results:

GHS criteria not met

Conclusions:

The acute oral LD50 was determined to be > 5000 mg/kg bw in rats.

Executive summary:

An acute oral toxicity study was performed in rats. The study was performed as GLP study similar to OECD guideline 401. Five rats/sex received a single oral gavage treatment with the test item in distilled water at 5000 mg/kg bw (10 mL/kg bw) and were then observed for 14 days. Animals were observed for 1 hour and at 3 hours after the administration and thereafter at least once a day (except holidays). Clinical signs were recorded at each observation. The animals were weighed prior to the administration and after 1, 2, 3, 7 and 14 days. A gross necropsy was performed at the termination of the experiment. All the rats were anesthetized with chloroform and sacrificed. No mortality, clinical signs or unusual changes in body weight were observed. Gross necropsy revealed no abnormality in any rats of either sex. The acute oral LD50 was determined to be > 5000 mg/kg bw.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

discriminating dose

Value:

5 000 mg/kg bw

Quality of whole database:

similar to OECD TG 401

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

30 September 1986 - 04 March 1987

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

GLP compliance:

yes

Test type:

traditional method

Limit test:

no

Species:

rat

Strain:

Crj: CD(SD)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Japan, Inc. (Atsugi, Kanagawa, Japan)
- Age at study initiation: 7 weeks old
- Weight at study initiation: males: 183 ± 5 g, females: 146 ± 8 g (at the start of the experiment)
- Housing: Group-housed (5 animals per cage) in stainless steel mesh cage (34 x 34 x 21 cm), which was placed for 4 hours in whole-body exposure chambers.
- Diet: standardised pelleted dry diet, MF (Oriental Yeast Co., Ltd.), ad libitum; no food during exposure
- Water: tap water ad libitum; no water during exposure
- Acclimation period: 1 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 24.5 - 25.7
- Humidity (%): 51 - 85.9
- Photoperiod (hrs dark / hrs light): 12 / 12

Route of administration:

inhalation: dust

Type of inhalation exposure:

whole body

Vehicle:

clean air

Mass median aerodynamic diameter (MMAD):

>= 3.7 - <= 4.5 µm

Geometric standard deviation (GSD):

>= 0.2 - <= 0.9

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: inhalation apparatus with pre-filter and dust generator
- Exposure chamber volume: 590 L
- Method of holding animals in test chamber: whole body exposure, cages were placed in the exposure camber for 4 hours
- Source and rate of air: 127 - 130 L/min
- System of generating particulates/aerosols: dust generator
- Method of particle size determination: Measurements of particle size of dust were carried out twice an hour during exposure. The constant volume (28 - 84 L) of dust was taken from the sample port of the chamber and led to Andersen Sampler (Dylec Co., Ltd.). The particles of each size were caught on each filter paper in the sampler. The actual concentration was determined by means of weighing the papers with the particles of each size range.
- Treatment of exhaust air: exhaust air was taken out from the bottom of the exposure chamber and discarded through shower cleaner and filters
- Temperature, humidity, pressure in air chamber: temperature: 24.5 - 25.7 °C, humidity: 51.1 - 85.9%,

TEST ATMOSPHERE
- Brief description of analytical method used: Measurements of actual concentration of dust were carried out twice an hour during exposure. The constant volume (28 - 84 L) of dust was taken from the sample port of the chamber and led to Andersen Sampler (Dylec Co., Ltd.). The particles of each size were caught on each filter paper in the sampler. The particle size distribution was determined by means of weighing the papers with the particles of each size range.
- Samples taken from breathing zone: no

Analytical verification of test atmosphere concentrations:

yes

Duration of exposure:

4 h

Concentrations:

nominal concentrations: 1.9, 3.8, 5.6, 7.6 and 9.4 mg/L
acutal concentrations: 0.5, 1.0, 1.5, 1.6 and 1.9 mg/L

No. of animals per sex per dose:

5

Control animals:

yes

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: observations: 1 hour and 3 hours after exposure, and at least once a day for 14 days thereafter; weighing: prior to exposure and on the 1st, 2nd, 3rd, 7th and 14th days of the observation period
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight

Key result

Sex:

male

Dose descriptor:

LC50

Effect level:

1.7 mg/L air (analytical)

Based on:

test mat.

Exp. duration:

4 h

Key result

Sex:

female

Dose descriptor:

LC50

Effect level:

1.9 mg/L air (analytical)

Based on:

test mat.

Exp. duration:

4 h

Mortality:

No deaths occurred in the control and the lower dosed groups (0, 0.5, 1.0 and 1.5 mg/L) in males. In females no deaths occurred in the control and the 0.5, 1.5 and 1.6 mg/L groups . In males, all animals of the 1.9 mg/L group died at the 1st day (One rat died during the exposure). In females, death occurred at the 1st and 2nd days in the 1.0 and 1.9 mg/L groups. Mortalities in the male groups of 1.0, 1.5, 1.6 and 1.9 mg/L were 0, 0, 0 and 100%, respectively, and those in the female groups of 0.5, 1.0, 1.5, 1.6 and 1.9 mg/1 were 0, 20, 0, 0 and 60%, respectively.

Clinical signs:

other: No toxic signs appeared in the control groups in either sex. Decreased motor activity, low sensitivity, hypotonia, ventral position, incontinence of urine, ataxia, ptosis, tremor and convulsion were observed in the dosed groups.

Remarks:

These toxic signs appeared within 1 day after the exposure. However, all toxic signs disappeared within 3 days after the exposure.

Body weight:

Body weight decrease and growth depression were observed in almost all female rats of all dosed groups and male rats in the 1.5 and 1.6 mg/L groups within 3 days after the exposure, however, their body weights increased thereafter. Net gains in treated animals were less than gains recorded in control animals.

Gross pathology:

In the gross necropsy, dark reddish lung was found in one dead rat. But, there were no significant changes in the other rats which died or survived until the termination of the observation period.

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

The LC50 value of the test item was determined to be 1.7 mg/L for males and 1.9 mg/L for females.

Executive summary:

An acute inhalation toxicity study was performed in male and female Crj:CD(SD) rats. The animal were divided into 9 dosed and 2 control groups, each group consisted of 5 rats, and the former groups were exposed to the test item and the latter to air only for 4 hours. The mean actual concentrations of the test item were 1.9, 1.6, 1.5 and 1.0 mg/L in males and females. The particle size of the test item was almost identical among the dosed groups (mean mass median diameters were 3.7 - 4.5 µm and most of the particles were smaller than 10 µm in diameter). The toxic signs observed in the rats exposed to the test item were decreased motor activity, low sensitivity, ataxia, ptosis, incontinence of urine, tremor, convulsion, hypotonia and ventral position. Body weight decrease and growth depression were observed for 1 - 3 days after the exposure in many rats of the dosed groups, however, their body weights increased thereafter. The mortalities in the 1.9, 1.6, 1.5 and 1.0 mg/L groups of males were 100, 0, 0 and 0% and those in the 1.9, 1.6, 1.5, 1.0 and 0.5 mg/L groups of females were 60, 0, 0, 20 and 0%. Dark reddish lung was found in one dead rat. The LC50 value of the test item was determined to be 1.7 mg/L for males and 1.9 mg/L for females.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LC50

Value:

1 700 mg/m³ air

Quality of whole database:

similar to OECD TG 403

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

18 May 1990 - 23 August 1990

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

GLP compliance:

yes

Test type:

fixed dose procedure

Limit test:

yes

Species:

rabbit

Strain:

other: Kbs:JW (Japanese-white)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Kitayama LABES Co., Ltd. (Kyoto, Japan)
- Age at study initiation: 11 weeks old in male and female at the application
- Weight at study initiation: 2466.0±161.9 g in males and 2447.4±149.9 g in females at the application
- Housing: individually in stainless steel mesh cages (W 35xD 50xH 35cm)
- Diet: pelleted diet, RC-4 (0riental Yeast Co., Ltd., Tokyo), ad libitum
- Water: tap water, ad libitum
- Acclimation period: Quarantine: 13 days prior to the application.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.9± 0.6
- Humidity (%): 64.0± 1.7
- Air changes (per hr): 18
- Photoperiod (hrs dark / hrs light): 12 / 12

Type of coverage:

semiocclusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- Area of exposure: The test item was spread on a piece of lint (12 x 14 cm) which was applied to the back of the animal.
- Type of wrap: elastic bandage (Elascot, TE-1902, Tokyo Eizai Lab. Co., Ltd.)

REMOVAL OF TEST SUBSTANCE
- Washing: the application site was washed with water
- Time after start of exposure: 24 h

TEST MATERIAL
- Amounts applied: male: 27.1 - 31.0 mg/cm2, female: 28.0 - 30.4 mg/cm2
- For solids, paste formed: no

Duration of exposure:

24 h

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

5

Control animals:

yes, concurrent no treatment

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: observations: 1 hour and at 3 hours after the application and thereafter at least once a day (except holidays); weighing: prior to the application and after 1, 2, 3, 7 and 14 days.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No death was found in any rabbits.

Clinical signs:

other: 4 males and 3 females in the dosed groups showed reddening of the application area. This sign continued for 2 days after the application.

Gross pathology:

No abnormality was observed in any rabbits of either sex.

Interpretation of results:

GHS criteria not met

Conclusions:

The acute dermal LD50 was determined to be > 2000 mg/kg bw.

Executive summary:

An acute dermal toxicity study was performed with the test item in Kbs:JW rabbits. Twenty animals were divided into 1 control and 1 dose group consisting of 5 rabbits in each sex. The test item was dermally applied to the animals of the dose group at 2000 mg/kg bw and the animals of the control group were treated the same manner as the animals of the dosed group except for the test substance application. 4 males and 3 females in the dose group showed reddening of the application area. This observation continued for 2 days after the application. Body weight was not affected by the treatment. No death was observed in any rabbits of either sex. No abnormality on necropsy was observed in any rabbits. The acute dermal LD50 was determined to be > 2000 mg/kg bw.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

similar to OECD TG 402

Additional information

Acute oral

An acute oral toxicity study was performed in rats. The study was performed as GLP study similar to OECD guideline 401. Five rats/sex received a single oral gavage treatment with the test item in distilled water at 5000 mg/kg bw (10 mL/kg bw) and were then observed for 14 days. Animals were observed for 1 hour and at 3 hours after the administration and thereafter at least once a day (except holidays). Clinical signs were recorded at each observation. The animals were weighed prior to the administration and after 1, 2, 3, 7 and 14 days. A gross necropsy was performed at the termination of the experiment. All the rats were anesthetized with chloroform and sacrificed. No mortality, clinical signs or unusual changes in body weight were observed. Gross necropsy revealed no abnormality in any rats of either sex. The acute oral LD50 was determined to be > 5000 mg/kg bw.

Acute inhalation

An acute inhalation toxicity study was performed in male and female Crj:CD(SD) rats. The animal were divided into 9 dosed and 2 control groups, each group consisted of 5 rats, and the former groups were exposed to the test item and the latter to air only for 4 hours. The mean actual concentrations of the test item were 1.9, 1.6, 1.5 and 1.0 mg/L in males and females. The particle size of the test item was almost identical among the dosed groups (mean mass median diameters were 3.7 - 4.5 µm and most of the particles were smaller than 10 µm in diameter). The toxic signs observed in the rats exposed to the test item were decreased motor activity, low sensitivity, ataxia, ptosis, incontinence of urine, tremor, convulsion, hypotonia and ventral position. Body weight decrease and growth depression were observed for 1 - 3 days after the exposure in many rats of the dosed groups, however, their body weights increased thereafter. The mortalities in the 1.9, 1.6, 1.5 and 1.0 mg/L groups of males were 100, 0, 0 and 0% and those in the 1.9, 1.6, 1.5, 1.0 and 0.5 mg/L groups of females were 60, 0, 0, 20 and 0%. Dark reddish lung was found in one dead rat. The LC50 value of the test item was determined to be 1.7 mg/L for males and 1.9 mg/L for females.

Acute dermal

An acute dermal toxicity study was performed with the test item in Kbs:JW rabbits. Twenty animals were divided into 1 control and 1 dose group consisting of 5 rabbits in each sex. The test item was dermally applied to the animals of the dose group at 2000 mg/kg bw and the animals of the control group were treated the same manner as the animals of the dosed group except for the test substance application. 4 males and 3 females in the dose group showed reddening of the application area. This observation continued for 2 days after the application. Body weight was not affected by the treatment. No death was observed in any rabbits of either sex. No abnormality on necropsy was observed in any rabbits. The acute dermal LD50 was determined to be > 2000 mg/kg bw.

Justification for classification or non-classification

Classification, Labeling, and Packaging Regulation (EC) No 1272/2008

The available data for acute toxicity are reliable and suitable for classification purposes under Regulation (EC) No 1272/2008. Based on this data, the substance is not considered to be classified for acute oral and dermal toxicity under Regulation (EC) No 1272/2008, as amended for the seventeenth time in Regulation (EU) 2021/849. The substance is harmonized classified for acute inhalation toxicity Cat.4 (H332) under Regulation (EC) No 1272/2008, as amended for the seventeenth time in Regulation (EU) 2021/849.